miR-17-3p Downregulates Mitochondrial Antioxidant Enzymes and Enhances the Radiosensitivity of Prostate Cancer Cells

Abstract

Radioresistance remains to be a major obstacle in the management of patients with advanced prostate cancer (PCa). We have identified a mature miR-17-3p processed from the 3′ arm of precursor miR-17, which appeared to be able to inhibit three major antioxidant enzymes located in mitochondria, i.e., manganese superoxide dismutase (MnSOD), glutathione peroxidase 2 (Gpx2), and thioredoxin reductase 2 (TrxR2). Here we show that upregulation of miR-17-3p remarkably sensitized PCa cells to ionizing radiation (IR). Reductions of the three antioxidants led to increasing cellular reactive oxygen species (ROS) accumulation as well as declining mitochondrial respiration. The miR-17-3p-mediated dysfunction of mitochondrial antioxidants apparently sensitizing IR therapy was manifested in vitro and in vivo. Substantially, the miR-17-3p effect on suppression of the antioxidants can be efficiently eliminated or attenuated by transfecting with either an miR-17-3p inhibitor or each of the related antioxidant cDNA expression constructs. Overall, in addition to the insights into the functional assessments for the duplex of miR-17-5p and miR-17-3p, the present study highlights the rigorous evidence that demonstrated suppression of multiple mitochondrial antioxidants by a single microRNA (miRNA), thereby providing a promising approach to improve radiotherapy for advanced PCa by targeting mitochondrial function.

microRNA‐16‐5p enhances radiosensitivity through modulating Cyclin D1/E1–pRb–E2F1 pathway in prostate cancer cells

“…However, radioresistance is a major challenge that limits the efficacy of radiotherapy (Chang et al, ). Emerging evidence indicate that miRNAs could influence the radiosensitivity of various cancer cells through interplaying with other biological processes such as cell proliferation, apoptosis, cell cycle checkpoints, autophagy, and so forth (Palacios et al, ; Pawlik & Keyomarsi, ; Shao et al, ; Xu et al, ). Thus we performed human miRNA probe hybridization chip analysis to examine the expression profiles of miRNA in LNCaP cells which were exposed to X‐rays and 12 C 6+ ions.…”

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

“…High levels of antioxidant molecules in tumors have been identified as factors that make antitumor therapy difficult in many previous studies [44,45]. erefore, targeting antioxidant mechanisms might be a good therapeutic strategy for efficient radiotherapy [46]. Recent studies have reported that antioxidant mechanisms can be regulated by mTOR signaling [47][48][49].…”

MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy

“…Major mitochondrial antioxidant enzymes, including SOD and Gpx2, have been shown to be inhibited by miR-17 [149]. Furthermore, studies unveiled that miR-17, upregulated through inflammatory processes [150], is involved in the pathogenesis of endothelial dysfunction in the context of obesity and diabetes [151,152].…”

“… Target Refs. miR-210 Unknown – EC apoptosis and atherosclerosis [ 125 ] ISCU 1,2 [ 124 ] miR-21 Up [ 130 , 131 ] Promotes ROS production [ 132 , 133 ] SOD [ 132 , 133 ] miR-551b Up [ [ 140 ] Enhances ROS accumulation [ 134 , 135 ] CAT, SOD [ 134 , 135 ] miR-200c Up [ 142 , 143 ] EC apoptosis, ROS accumulation and senescence [ 144 , 145 ] PRDX2 [ 144 ] miR-17 Up [ 151 , 152 ] EC dysfunction [ 151 , 152 ] SOD, Gpx2 [ 149 ] miR-23b Up [ ...…”